The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All publications are incorporated by reference in their entirety.
9-(2-phosphonylmethoxyethyl)adenine (PMEA) and related analogues (U.S. Pat. No. 4,808,716; U.S. Pat. No. 5,142,051; De Clercq, et al., Antiviral Res. 8(5–6):261–72 (1987)) are phosphonic ac exhibit antiviral activity, including activity against hepatitis B and HIV. The dipivaloyloxy methylene ester of PMEA (“Bis POM PMEA”) is in clinical trials for the treatment of hepatitis B. (Benhamou, et al., Lancet 358(9283):718–23 (2001)) PMEA is thought to act by blocking DNA polymerase of HBV. In addition, some studies have shown that these compounds also show anticancer activity. (Murono, et al., Cancer Res., 61(21):7875–7 (2001)) The biologically active compound is thought to be the diphosphate, such as PMEApp, which is produced from the phosphonic acid most likely as result of specific mammalian intracellular kinases.
Compounds containing phosphonic acids and their salts are highly charged at physiological pH and therefore frequently exhibit poor oral bioavailability, poor cell penetration and limited tissue distribution (e.g., CNS). In addition, these acids are also commonly associated with several other properties that hinder their use as drugs, including short plasma half-life due to rapid renal clearance, as well as toxicities (e.g., renal, gastrointestinal, etc.) (e.g., Antimicrob Agents Chemother. 42(5): 1146–50 (1998)).
For example, PMEA exhibits a very low volume of distribution, presumably due to its high negative charge. In humans, 98% of the dose is excreted renally as a result of the presence of organic anion transporters on the basolateral surface of the kidney tubule cells which help facilitate the renal clearance of PMEA. PMEA therapy is associated with severe renal toxicity possibly due to the exposure and accumulation of PMEA and related phosphorylated species in the kidney. Thus, there is a need for means to reduce the toxicity of PMEA and related analogues.
Cyclic phosphonate esters have also been described for PMEA and related analogues. The numbering for these cyclic esters is shown below:
Unsubstituted cyclic 1′,3′-propanyl esters of PMEA were prepared but showed no in vivo activity. EP 0 481 214 B1 discloses examples of cyclic prodrugs of PMEA wherein the 1′ and 3′ positions are unsubstituted. The application and a subsequent publication by the inventors (Starrett et al., J. Med. Chem. 37:1857–1864 (1994)) further disclose their findings with the compounds, namely that these compounds showed no oral bioavailability and no biological activity. The compounds were shown to be unstable at low pH, e.g., the cyclic 2′,2′-difluoro-1′,3′-propane ester is reported to be hydrolytically unstable with rapid generation of the ring-opened monoester.
Cyclic prodrugs with aryl groups at 1′ are described for phosphonates that are known to be particularly useful in glucose lowering activity and therefore are useful in treating diabetes. (U.S. Pat. No. 5,658,889, WO 98/39344, WO 98/39343, and WO 98/39342) In addition, U.S. Pat. No. 6,312,662 discloses the use of this strategy for the liver-specific delivery of various drugs and compound classes to the liver for the treatment of patients with liver diseases such as hepatitis B and hepatocellular carcinoma.
Furthermore, diseases of the liver, such as hepatitis and liver cancer, remain poorly treated with current therapies due to dose-limiting extrahepatic side effects or inadequate delivery of chemotherapeutic agents to the target tissue.